EAST 501 Lecture Notes - Lecture 14: Male Contraceptive, Hypokalemia, Hepatitis
21 Jun 2018
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Feb 9th – Lec 14 Robaire
Male contraception
1
NON-HORMANL SUPPRESSION OF SPERM PRODUCTION – GOSSYPOL
- prohibited as feed for sheep in the US in the 1950s
- made its way as a replacement oil in China à in one province, a physician noticed that a lot of his patients were
infertile à tracked it down to the fact that the province changed its source of oil to cotton seed oil
- cotton seed oil extract à daily pill à like a mint that dissolves in mouth
- suppresses sperm production
- no anti-androgenic side effect; no effect on libido (non-hormonal)
- started doing long term studies and looking at the reversibility
o the reversibility gets worse with time
o the number of subjects who stayed in the trials decreased substantially
o reversibility depends on the length of exposure (very complex molecule)
o irreversible in some men
o hypokalemic effect à decrease serum K
§ this leads to muscle pain (this was the biggest problem that they had)
§ affects the NS and the heart à had a couple people die due to heart problems à not a good
sign for a contraceptive
o therapeutic index of ~10
- wanted to make an analogue that would dissociate the hypokalemic effect from the anti-spermatogenic effect
o made thousands of molecules
o they were not able to dissociate the different functions
o study lasted ~11years à 100M dollars spent
§ this generated a lot of news
o however…
§ inhibition of cell proliferation went along with the effect on p53 à stabilizing p53 à causes
DNA damage
§ prevents metastasis of many cancer types
§ activates mitochondrial pathway of apoptosis
§ intrinsic effect à could not differentiate the side effects
- mechanisms by mito and p53 à stabilizing p53 and activating the apoptosis pathway through the mitochondria
LONIDAMINE
- inhibit glycolysis and mitochondrial respiration
- initially developed as a suppressor of spermatogenesis
- we know that glycolysis and mitochondrial function are critical for sperm function à if you can inhibit the
isozymes of glycolysis that are found in sperm … you could have something that you selectively affect sperm and
not any other cell à not as specific as they would like it to be
- now used as an anticancer drug
- it has no anti-mitotic activity, by sensitized tumors to chemo-, radio-, and photodynamic therapy
o enhances the activity of chemotherapeutic agents
- not as specific as they wanted
- but side effects include:
o muscular pain (worst side effect)
o testicular pain (worst side effect)
o vomiting (transient)
o elevation of liver enzymes
o liver damage
o MAJOR SIDE EFFECTS
Feb 9th – Lec 14 Robaire
Male contraception
2
- modified the structure à ADJUDIN
o analogue of Ionidamine
o no effects on LH, FSH, T
o no acute toxicity, genotoxicity, or mutagenesis
o disrupts adhesion of spermatids to Sertoli cells à
induces release of immature spermatids
o “The male patch”
§ non-hormonal male contraceptive
§ non-toxic Ionidamine analog
(2,4dicholorobenzyl-1Hydroxy-indazolecarbohydrazide)
o it prevents cell-cell communication between adjacent cells
§ the tight cell-cell interaction between the cell
is disrupted
§ there are specific cell junction molecules that
are inhibited
§ what you end up doing is getting early release
of germ cells à makes sure that you don’t
have matured sperm being produced
- However,
o it dissociated cells in other tissues as well, particularly in the liver
o in rat sub-chronic toxicity study, 30% of males displayed signs
of liver inflammation (huge amounts) and skeletal muscle atrophy à
working on more analogues
§ the liver inflammation was not initially observable in the
lower doses for the treatment that they initially tried,
but at the higher doses it was very apparent
o this was only shown in the chronic treatment that they later tried
o they are still making the analogues (now ~1200 analogues) of Adjuvin
o some of the cell adhesion molecules in the testis are specific to the testes so those need to be
specifically targeted (not target the regular cell adhesion molecules)
RETINOIC ACID
- drugs that cause azoospermia:
o in the 1970s they had identified a list of molecules as wonderful male contraceptive agents à they all
inhibit spermatogenesis
§ many of them are used for cancer treatment (or other conditions) and that they inhibit
spermatogenesis is not a surprise à they are non-hormonal anti-spermatogenic agents
§ one of them is a derivative of an antibiotic - WIN 18,446
• tested with men in the 1950-60s in a prison in Oregon à it worked
• spermatogenesis down to zero
• no side effects or change in hormone levels
• did a Phase I clinical trial (with young men) à all the men came back really sick
• it works like disulfiram
• it inhibits the enzyme ALDH1A1 = there is a buildup of aldehyde dehydrogenase à
acetaldehyde build up
• in the testes there are two forms of the same enzyme: ALDH1A1 and ALDH1A2
o if you give WIN 18,446 what you get in the liver is a transient suppression, in the
testes there is a much greater suppression
